P596: CLINICAL IMPACT OF TP53 DISRUPTION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH A BCR INHIBITOR. A CAMPUS CLL EXPERIENCE
Authors: R. Bomben, F. M. Rossi, F. Vit, T. Bittolo, A. Zucchetto, R. Papotti, E. Tissino, F. Pozzo, M. Degan, E. Zaina, I. Cattarossi, P. Nanni, R. Marasca, G. Reda, L. Laurenti, J. Olivieri, A. Chiarenza, L. Ballotta, A. Cuneo, M. Gentile, F. Morabito, A. Tafuri, F. Zaja, R. Foà, F. Di Raimondo, G. Del Poeta, V. Gattei
Journal: HemaSphere (2022)

Background: In chronic lymphocytic leukemia (CLL), the presence of TP53 aberration (mutations and/or deletion) predicts an increased risk of relapse and death after chemo-immunotherapy (CIT). Although TP53 deletion and mutations mostly co-occur and are considered equal prognosticators, the clinical impact of isolated or concomitant mutations and deletions remains unclear in the context of targeted agents. Aims: To investigate the clinical relevance of isolated or concomitant TP53 aberrations in a large cohort of CLL patients treated with BCR inhibitors. Methods: In the framework of an institutional Italian multicenter working group on CLL (Campus CLL), a retrospective analysis of 229 CLL patients (51 treatment naïve, and 178 relapsed/refractory) treated with ibrutinib was carried out. All patients referred to a single institution for del17p analyses by FISH (167-kb 17p13 orange probe, MetaSystems) and TP53 mutations by NGS, both analyses carried out on CD19-purified (>85% pure) CLL samples within 6 months prior the start of ibrutinib treatment. The median follow-up from ibrutinib treatment was 36.3 months (95% CI 29.5-41.5 months). Overall survival (OS) and progression free survival (PFS) were computed from the start of ibrutinib treatment. Results: In the CLL cohort, 76 patients with del17p showed a trend for inferior OS respect to wt cases (P=0.0662, Fig.1A), while a significant correlation was found with PFS (P=0.0162). With regard to TP53 mutations, 296 TP53 mutations were found in 126 patients (range of mutations/patients 1-11). As with CIT, TP53-mutated patients, irrespective of VAF (Fig.1B), experienced a significantly worse OS and PFS than wt cases also by univariate analyses (P=0.0160, and P=0.0378, respectively). The combination of del17p with TP53 mutation data identified 95 cases with no TP53 aberrations, 8 cases del17p only, 58 cases TP53-mutated only, and 68 cases bearing both del17p deletion and TP53 mutation (Fig.1CD). Only patients with concomitant TP53 mutations and del17p experienced significantly shorter OS and PFS compared to TP53wt cases (P=0.0122, and P=0.0076, respectively; Fig.1CD). Conversely, patients presenting a single aberration showed no significant differences compared to wt patients (Fig.1CD). The simultaneous presence of TP53 mutations and del17p remained an independent predictor factor both for OS and PFS by multivariate analysis, together with the previous therapy lines (0-1 vs. >1), and anemia. The evolution of TP53-mutated clones was assessed by longitudinal NGS analysis of sequential PB samples collected from 38 patients (16 relapsed, and 22 on treatment) corresponding to 127 TP53 mutations. Among relapsed cases, 7 showed a prominent expansion of the TP53-mutated clone, 8 remained stable, and the remaining case displayed an evident decrease (Fig.1E). In non-relapsed patients, 3 cases presented an increase of TP53 mutations, 13 remained stable, and 6 showed a reduction (Fig.1F), with no significant difference compared to relapsed cases (P=0.0623, c2 test). BTK and PLCG2 mutations were found in 9/16 (56%) relapsed cases and in 3/22 (14%) patients still on ibrutinib (P=0.0492, c2 test). Of note, only 3/7 relapsed cases that presented a positive selection for TP53 mutations showed the presence of BTK mutations at the time of relapse. Image:Summary/Conclusion: This retrospective study indicates that only the concomitant presence of TP53 mutations and deletion is an independent negative prognostic factor for OS and PFS in patients with CLL on ibrutinib treatment; the simultaneous investigation of del17p and TP53 mutations may lead to a more precise risk assessment.